Soticlestat

Soticlestat
Clinical data
Other names	TAK-935; OV-935
Routes of; administration	By mouth
Identifiers
	IUPAC name (4-benzyl-4-hydroxypiperidin-1-yl)-(2-pyridin-4-ylpyridin-3-yl)methanone;
CAS Number	1429505-03-2;
PubChem CID	73437845;
ChemSpider	68007185;
UNII	1766MU795L;
KEGG	D11590;
ChEMBL	ChEMBL4298172;
Chemical and physical data
Formula	C23H23N3O2
Molar mass	373.456 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1CN(CCC1(CC2=CC=CC=C2)O)C(=O)C3=C(N=CC=C3)C4=CC=NC=C4;
	InChI InChI=1S/C23H23N3O2/c27-22(20-7-4-12-25-21(20)19-8-13-24-14-9-19)26-15-10-23(28,11-16-26)17-18-5-2-1-3-6-18/h1-9,12-14,28H,10-11,15-17H2; Key:XKUZMIUSBMCVPP-UHFFFAOYSA-N;

Soticlestat (TAK-935, OV-935) is an experimental anticonvulsant and cholesterol 24-hydroxylase inhibitor being investigated as a treatment for Dravet syndrome, Lennox–Gastaut syndrome, tuberous sclerosis complex, dup15q syndrome, and CDKL5 deficiency disorder.^[1]^[2] The development rights to the drug were purchased by Takeda Pharmaceuticals from Ovid Therapeutics in 2021.^[3]

Soticlestat was designated as an orphan drug by the FDA in 2017 for the treatment for both Dravet syndrome and Lennox–Gastaut syndrome.^[4]

Mechanism of action

Soticlestat functions by blocking cholesterol 24-hydroxylase (CH24H, also known as CYP46A1), an enzyme in the brain that converts cholesterol to the oxysterol 24S-hydroxycholesterol (24S-HC). Reduction of 24S-HC has been shown to reduce glutamatergic signaling, which reduces seizures.^[1]^[2] Soticlestat may also have neuroprotective and anti-inflammatory properties via glial cell modulation.^[2]

Clinical trials

Soticlestat has been assessed in clinical trials for refractory epilepsy associated with Dravet syndrome and Lennox–Gastaut syndrome. The Phase 2 ELEKTRA study indicated that soticlestat was well tolerated and reduced seizure frequency.^[5]

In the Phase 3 SKYLINE clinical study, Takadea reported that topline data showed soticlestat plus standard of care narrowly missed its primary endpoint of reducing convulsive seizure frequency in patients with Dravet syndrome. However, it demonstrated clinically significant effects on several key secondary endpoints, including responder rates and measures of caregiver and clinician global perceptions of improvement. In the separate Phase 3 SKYWAY trial, soticlestat did not meet its primary endpoint of reducing major motor drop seizures in Lennox–Gastaut syndrome. Both studies reported a favorable safety and tolerability profile for soticlestat.^[6]

References

^ ^a ^b Hong W, Haviland I, Pestana-Knight E, Weisenberg JL, Demarest S, Marsh ED, Olson HE (June 2022). "CDKL5 Deficiency Disorder-Related Epilepsy: A Review of Current and Emerging Treatment". CNS Drugs. 36 (6): 591–604. doi:10.1007/s40263-022-00921-5. PMC 9876658. PMID 35633486.
^ ^a ^b ^c Pong AW, Ross J, Tyrlikova I, Giermek AJ, Kohli MP, Khan YA, Salgado RD, Klein P (March 2022). "Epilepsy: expert opinion on emerging drugs in phase 2/3 clinical trials". Expert Opinion on Emerging Drugs. 27 (1): 75–90. doi:10.1080/14728214.2022.2059464. PMID 35341431. S2CID 247763576.
^ "Takeda buys epilepsy treatment rights from Ovid for up to $856 million". Reuters. 3 March 2021. Retrieved 2 October 2023.
^ Pena, Ana (22 October 2019). "Soticlestat Can Reduce Seizure Frequency in Adults With Dravet, Other Rare Epilepsies, Initial Data Shows". Dravet Syndrome News. Retrieved 2 October 2023.
^ Hahn CD, Jiang Y, Villanueva V, Zolnowska M, Arkilo D, Hsiao S, Asgharnejad M, Dlugos D (October 2022). "A phase 2, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of soticlestat as adjunctive therapy in pediatric patients with Dravet syndrome or Lennox–Gastaut syndrome (ELEKTRA)". Epilepsia. 63 (10): 2671–2683. doi:10.1111/epi.17367. PMC 9804149. PMID 35841234.
^ "Takeda Announces Phase 3 Topline Results for Soticlestat". Takeda Pharmaceuticals. 17 June 2024. Retrieved September 10, 2024.

[pmid35633486-1] Hong W, Haviland I, Pestana-Knight E, Weisenberg JL, Demarest S, Marsh ED, Olson HE (June 2022). "CDKL5 Deficiency Disorder-Related Epilepsy: A Review of Current and Emerging Treatment". CNS Drugs. 36 (6): 591–604. doi:10.1007/s40263-022-00921-5. PMC 9876658. PMID 35633486.

[pmid35341431-2] Pong AW, Ross J, Tyrlikova I, Giermek AJ, Kohli MP, Khan YA, Salgado RD, Klein P (March 2022). "Epilepsy: expert opinion on emerging drugs in phase 2/3 clinical trials". Expert Opinion on Emerging Drugs. 27 (1): 75–90. doi:10.1080/14728214.2022.2059464. PMID 35341431. S2CID 247763576.

[Reuters_2021-3] "Takeda buys epilepsy treatment rights from Ovid for up to $856 million". Reuters. 3 March 2021. Retrieved 2 October 2023.

[Pena_2019-4] Pena, Ana (22 October 2019). "Soticlestat Can Reduce Seizure Frequency in Adults With Dravet, Other Rare Epilepsies, Initial Data Shows". Dravet Syndrome News. Retrieved 2 October 2023.

[pmid35841234-5] Hahn CD, Jiang Y, Villanueva V, Zolnowska M, Arkilo D, Hsiao S, Asgharnejad M, Dlugos D (October 2022). "A phase 2, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of soticlestat as adjunctive therapy in pediatric patients with Dravet syndrome or Lennox–Gastaut syndrome (ELEKTRA)". Epilepsia. 63 (10): 2671–2683. doi:10.1111/epi.17367. PMC 9804149. PMID 35841234.

[Takeda_June_2024-6] "Takeda Announces Phase 3 Topline Results for Soticlestat". Takeda Pharmaceuticals. 17 June 2024. Retrieved September 10, 2024.

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